An Exploratory Study of Pembrolizumab Plus Entinostat in Non-Inflamed Stage III/IV Melanoma

This is an exploratory (n=10-12 evaluable patients), open-label, single-arm, phase II study in patients with 'non-inflamed' unresectable regional or distant metastatic melanomas irrespective of prior treatment with PD-1/PD-L1 pathway inhibitors. The primary endpoint is to assess the incidence of histopathologic conversion of non-inflamed melanomas from patients with metastatic melanoma to 'inflamed' melanoma following single-agent entinostat "priming" (entinostat monotherapy). More specifically, patients with metastatic melanomas that have no evidence of tumor-infiltrating or tumor-associated lymphocytes (TIL/TAL), based on standard hematoxylin and eosin (H\&E) staining of representative tumor sections (non-inflamed melanomas) will receive weekly entinostat for 3 weeks in cycle 1 (entinostat monotherapy; 5mg PO, qwk on D1, D8, D15 of cycle 1; cycle length = 21 days). Mandatory tumor tissue biopsies will be performed in the end of cycle 1, beginning of cycle 2 (day 21±2 days), immediately before treatment with concurrent entinostat (once weekly × 3) and pembrolizumab (200 mg q3wks) in cycles 2-9 (see section 5.2.1 drug dosing schema). Correlative studies will be performed at baseline and in the end of cycle 1, beginning of cycle 2 (day 21±2 days) to assess whether: (a) 3 weeks of entinostat monotherapy converts TIL/TAL-absent melanomas to TIL/TAL-present by histopathologic (H\&E stain) analysis, (b) 3 weeks of single-agent entinostat induces changes in gene expression profiling by assessing distinct signatures as defined by RNA-sequencing signatures (RNA-seq; 'immune-high', innate anti-PD-1 resistance, and epigenetic 1-3), (c) 3 weeks of single-agent entinostat induces changes in histone-accessible DNA by performing formaldehyde-assisted isolation of regulatory elements (FAIRE)4, (d) conversion of non-inflamed to inflamed melanomas by single-agent entinostat and/or antitumor response to the entinostat-pembrolizumab combination is associated with a baseline signature that consists of distinct somatic mutation gene profile, global histone modification profile in melanoma tissue or peripheral blood mononuclear cells (PBMC), and/or abundance of entinostat targets in melanoma cells (HDAC 1, 2, 3, and 11). Up to 12 evaluable patients will be treated with entinostat plus pembrolizumab for up to 27 weeks (approximately 6 months) based on clinical benefit. Patients who continue to have clinical benefit at 27 weeks may continue therapy with pembrolizumab or any other PD-1/PD-L1 inhibitor, as per standard of care.Secondary exploratory endpoints involve: (a) assessment of antitumor response of entinostat administered concurrently with pembrolizumab at week 10 (or earlier if patient progresses), based on response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). (b) assessment of the progression-free survival (PFS) rate at 27 weeks (approximately 6 months) of the entinostat-pembrolizumab combination. (c) determine the safety of the entinostat-pembrolizumab combination in patients with metastatic melanoma per NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE). (d) assessment of other exploratory biomarkers in tumor tissue and peripheral blood.